Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo, Japan.

Abstract

Selective serotonin reuptake inhibitors (SSRIs) are widely used antidepressants, but the mechanisms by which they influence behavior are only partially resolved. Adult hippocampal neurogenesis is necessary for some of the responses to SSRIs, but it is not known whether maturedentategyrusgranulecells (DG GCs) also contribute. We deleted the serotonin 1A receptor (5HT1AR, a receptor required for the SSRI response) specifically from DG GCs and found that the effects of the SSRI fluoxetine on behavior and the hypothalamic-pituitary-adrenal (HPA) axis were abolished. By contrast, mice lacking 5HT1ARs only in young adult-born GCs (abGCs) showed normal fluoxetine responses. Notably, 5HT1AR-deficient mice engineered to express functional 5HT1ARs only in DG GCs responded to fluoxetine, indicating that 5HT1ARs in DG GCs are sufficient to mediate an antidepressantresponse. Taken together, these data indicate that both mature DG GCs and young abGCs must be engaged for an antidepressantresponse.

5HT1ARs in DG GCs are required for the neuroendocrine response to fluoxetine. a) Timeline for panels b–c. Control or POMC-Cre/fl1A mice were administered daily fluoxetine (18 mg/kg) or vehicle starting at 8 weeks of age. Blood was collected from mice in their home cage three weeks after the start of fluoxetine treatment and then again from the same mice one week later 45 minutes after EPM exposure. n=6 per group. b) Home cage plasma corticosterone levels. There were no differences (Two-Way ANOVA). c) Plasma corticosterone levels after EPM exposure. Corticosterone levels were analyzed by Two-Way ANOVA (F(1,20)=5.585, p=.0284). * indicates p=.0117 (Tukey’s). d) Timeline for panels e–f. Nestin-CreER/fl1A mice were pretreated with 200mg/kg tamoxifen or vehicle (three days, twice per day). Daily fluoxetine (18 mg/kg) or vehicle treatment began either when the mice were 8 weeks old (left, concurrent with the tamoxifen) or when they were 11 weeks old (right). Blood was collected from mice in their home cage three weeks after the start of fluoxetine treatment and then again from the same mice one week later 45 minutes after EPM exposure. n=6 per group. e) Home cage plasma corticosterone levels. There were no differences (Two-Way ANOVA). f) Plasma corticosterone levels after EPM exposure. *** indicates p<.0001 (Two-Way ANOVA; treatment effect only). Bars and error bars throughout the figure represent mean ± SEM. g) Timeline for panels h–i. 1A KO or DG-1A+ mice were administred daily fluoxetine (18 mg/kg) or vehicle starting at 8 weeks of age. Blood was collected from mice in their home cage three weeks after the start of fluoxetine treatment and then again from the same mice one week later 45 minutes after EPM exposure. n=6 per group. h) Home cage plasma corticosterone levels. There were no differences (Two-Way ANOVA). i) Plasma corticosterone levels after EPM exposure. Corticosterone levels were analyzed by Two-Way ANOVA (F(1,20)=8.878, p=.0074). ** indicates p=.0079 (Tukey’s). Mean lines and error bars throughout the figure represent mean ± SEM. V: Vehicle. F: Fluoxetine. F(8): Fluoxetine (8 wks). F(11): Fluoxetine (11 wks).